Obsessive compulsive disorder (OCD) is a leading cause of illness related disability. More effective treatments with fewer side effects and faster onset of action are desperately needed. Cognitive behavioral therapy is highly effective, but not easily disseminated and difficult for many patients to execute. Serotonin reuptake inhibitors (SRIs) are only moderately effective in some patients and have a long lag time (610 weeks) before symptom reduction. SRIs also commonly cause sexual dysfunction, a major reason for patient discontinuation. The only medications proven to augment SRIs is the addition of antipsychotics, which help up to a third of patients; however, the side effects of weight gain and sedation also lead to high rates of discontinuation. My goal is to integrate the latest basic science and pathophysiology of disease and to use that knowledge to identify and test new drugs directed at underlying neurobiological mechanisms of OCD and related disorders. My focus during this Mentored PatientOriented Research Career Development Award (K23) is the glutamate system because recent human and animal data implicate abnormal glutamatergic functioning in cortico-striatial circuits in OCD. Moreover, medications thought to modulate the glutamate system have shown promise in open label trials. The Career Development Plan will focus on developing: 1) expertise in the phenomenology and neurobiology of OCD to identify novel treatment targets; 2) skill in the design, conduct, and analysis of clinical trials to test novel compounds; 3) in-depth knowledge of magnetic resonance spectroscopy (MRS) methods to test the effects of treatments on the brain. The Research Plan will test two putative glutamate modulators in OCD: Project #1 is a randomized trial of minocycline, thought to act through glial mechanisms, to augment SRIs in OCD patients. Pilot data suggest that it is well tolerated and may have dramatic symptom reduction in some patients. Advantages of minocycline are low cost, FDA approval in children e12 (for long-term treatment of acne), and less side effects than antipsychotics. The goal is to examine the effects of minocycline as an adjunct to SRIs to determine if minocycline is worth pursuing in an R01 application. Project #2: is a randomized trial of ketamine, a glutamate receptor antagonist, in drug free OCD patients who have failed prior SRI trials. The goal is to determine safety and feasibility of ketamine in OCD and to explore ketamine effects on OCD symptoms and on glutamate measures in the anterior cingulate cortex. Together these projects will help examine the role of the glutamatergic system in OCD and explore novel treatments for OCD; promising data from either project will lead to future R01 studies. In the process, I will acquire skills and experience necessary to launch my career as an independent, patient oriented researcher. This study promotes the NIMH strategic plan by testing novel interventions for OCD (Strategy 3.1) and exploring a potential marker of treatment response (Strategy 1.3).